The long-term objective of this application is to understand the molecular and cellular mechanisms underlying cartilage formation and repair. Degeneration of the joint cartilage leads to osteoarthritis (OA), the most common form of arthritis affecting middle-aged and elderly people. The cartilage loss is caused, at least in part, by the failure of chondrocytes to repair the cartilage matrix and reduced proliferative capacity of the chondrocytes. The mechanisms that regulate chondrocyte proliferation and its biosynthetic activity, however, are poorly understood. The applicant has found that Zacl, a recently characterized zinc finger protein, is predominantly localized in the developing chondrogenic tissue during mouse embryogenesis. Zacl possesses anti-proliferative activity and is a potential tumor suppressor gene, suggesting that it may have a role in regulating chondrocyte proliferation and differentiation, and cartilage gene expression. This application proposes to investigate the role of Zacl in chondrogenesis using an established in vitro model culture system for chondrocyte differentiation. The effects of over-expression and inhibition of Zacl during in vitro chondrogenesis will be studied, and the genes regulated by Zacl in chondrocyte differentiation will be investigated. These studies will provide a better understanding of regulatory factors important for cartilage formation and repair.